Luke A J O'Neill

Trinity College Dublin, Dublin, Leinster, Ireland

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Publications (246)2301.82 Total impact

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    ABSTRACT: TLR4 interactor with leucine-rich repeats (TRIL) is a brain-enriched accessory protein that is important in TLR3 and TLR4 signaling. In this study, we generated Tril(-/-) mice and examined TLR responses in vitro and in vivo. We found a role for TRIL in both TLR4 and TLR3 signaling in mixed glial cells, consistent with the high level of expression of TRIL in these cells. We also found that TRIL is a modulator of the innate immune response to LPS challenge and Escherichia coli infection in vivo. Tril(-/-) mice produce lower levels of multiple proinflammatory cytokines and chemokines specifically within the brain after E. coli and LPS challenge. Collectively, these data uncover TRIL as a mediator of innate immune responses within the brain, where it enhances neuronal cytokine responses to infection.
    Journal of immunology (Baltimore, Md. : 1950). 07/2014;
  • Luke A J O'Neill
    Nature Immunology 03/2014; 15(4):314-5. · 26.20 Impact Factor
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    ABSTRACT: Background: Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens, and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4 and MyD88 mediated signalling to orchestrate downstream inflammatory responses. While MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Methods: Colitis was induced in wild type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total-body gamma irradiation followed by transplantation of bone marrow cells. Results: In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neo-formations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumours. Mal(-/-) and WT bone marrow chimeras demonstrated that non-haematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Conclusions: Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in non-haematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.
    AJP Gastrointestinal and Liver Physiology 03/2014; · 3.65 Impact Factor
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    ABSTRACT: The apoptosis associated speck-like protein containing a CARD (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML- deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following BMDM infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively our data indicate that PML limits ASC function, retaining ASC in the nucleus.
    Journal of Biological Chemistry 01/2014; · 4.65 Impact Factor
  • Susan R Quinn, Luke A O'Neill
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    ABSTRACT: Recent studies have shown an important interplay between Interleukin 10 (IL-10) and microRNAs. IL-10 can be directly post-transcriptionally regulated by several microRNA, including miR-106a, miR-4661, miR-98, miR-27, let7 and miR-1423p/5p. miRNA targeting of IL-10 has been suggested to play a role in autoimmune and inflammatory diseases such as SLE, reperfusion injury and asthma. Another miRNA, miR-21, has been shown to indirectly regulate IL-10 via downregulation of the IL-10 inhibitor PDCD4. The targeting of IL-10 in this way has been linked to host defence modulation by Mycobacterium leprae. Viral miRNAs, such as miR-K12-3 from Kaposi's sarcoma-associated herpesvirus (KSHV), can also decrease IL-10 to promote tumour development. Finally this interplay can operate in a feedback loop, with IL-10 capable of regulating microRNAs, upregulating those that can contribute to exerting the anti-inflammatory response, such as miR-187, and downregulating those that are highly pro-inflammatory, such as miR-155. Understanding the two-way regulation between miRNA and IL-10 is giving rise to new insights into this important cytokine.
    Current topics in microbiology and immunology 01/2014; 380:145-55. · 4.86 Impact Factor
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    ABSTRACT: The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.
    PLoS ONE 01/2014; 9(6):e100816. · 3.53 Impact Factor
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    ABSTRACT: MicroRNA-155 (miR-155) is highly expressed in many cancers such as B cell lymphomas and myeloid leukaemia, and inflammatory disorders such as rheumatoid arthritis, atopic dermatitis and multiple sclerosis. The role of miR-155 as both a promoter of inflammation and an oncogenic agent provides a clear need for miR-155 itself to be stringently regulated. We therefore investigated the transcriptional regulation of miR-155 in response to the respective pro- and anti-inflammatory mediators LPS and IL-10. Bioinformatic analysis revealed Ets binding sites on the miR-155 promoter, and we found that Ets2 is critical for miR-155 induction by LPS. Truncation and mutational analysis of the miR-155 promoter confirmed the role of the Ets2 binding site proximal to the transcription start site for LPS responsiveness. We observed increased binding of Ets2 to the miR-155 promoter and Ets2 deficient mice displayed decreased induction of miR-155 in response to LPS. IL-10 inhibited the induction of Ets2 mRNA and protein by LPS, thereby decreasing Ets2 function on the pri-155 promoter. We have thus identified Ets2 as a key novel regulator in both the positive and negative control of miR-155 in the inflammatory response.
    Journal of Biological Chemistry 12/2013; · 4.65 Impact Factor
  • Evanna Mills, Luke A J O'Neill
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    ABSTRACT: Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1α (HIF-1α) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD(+) and citrate whose roles have expanded beyond metabolism and into signaling.
    Trends in cell biology 12/2013; · 12.12 Impact Factor
  • Luke A J O'Neill
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    ABSTRACT: The Nlrp3 inflammasome is a key controller of the proinflammatory cytokine IL-1β. Iyer and colleagues (2013) demonstrate that Nlrp3 activators promote an interaction between cardiolipin in mitochondria and Nlrp3. Cardiolipin is thus a hydrophobic danger signal that, upon translocation to the outer mitochondrial membrane, activates Nlrp3, promoting inflammation.
    Cell metabolism 11/2013; 18(5):610-2. · 17.35 Impact Factor
  • Eva M Palsson-McDermott, Luke A J O'Neill
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    ABSTRACT: Inflammatory immune cells, when activated, display much the same metabolic profile as a glycolytic tumor cell. This involves a shift in metabolism away from oxidative phosphorylation towards aerobic glycolysis, a phenomenon known as the Warburg effect. The result of this change in macrophages is to rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins. In addition, a rise in certain tricarboxylic acid cycle intermediates occurs notably in citrate for lipid biosynthesis, and succinate, which activates the transcription factor Hypoxia-inducible factor. In this review we take a look at the emerging evidence for a role for the Warburg effect in the immune and inflammatory responses. The reprogramming of metabolic pathways in macrophages, dendritic cells, and T cells could have relevance in the pathogenesis of inflammatory and metabolic diseases and might provide novel therapeutic strategies.
    BioEssays 09/2013; · 5.42 Impact Factor
  • Nicholas J Bernard, Luke A O'Neill
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    ABSTRACT: The family of type 1 transmembrane proteins known as Toll-like receptors (TLRs) provide early immune system recognition and response to infection. In order to transmit their signal to the nucleus and initiate activation of pro-inflammatory and anti-microbial genes, TLRs must initiate a cytoplasmic signalling cascade, which is alternately controlled by 6 known signalling adaptors. These signaling adaptors are crucial for activating the correct immune response to any given TLR / pathogen interaction. This review will focus on one of those adaptors, MyD88 adaptor-like (Mal), also known as TIRAP. Mal is critical for signalling by the best studied of the TLRs, the Gram negative bacterial lipopolysaccharide (LPS) sensor, TLR4. Mal's role in TLR2 signalling in response to activation of the bacterial lipopeptide receptor, TLR2, is more contentious. Mal is a component of the so-called 'MyD88-dependent pathway' in TLR4 signalling. Recent advances in our understanding of the signalling pathways downstream of Mal highlight MyD88-indpendent roles, thus positioning Mal as multifunctional and integral for the molecular control of bacterial infections as well as inflammatory diseases. Here we describe the sequence of molecular events involved in the signalling pathways controlled by Mal, and the importance of Mal in driving host protection against a variety of bacteria, with specific attention to the evidence for Mal's role in TLR2 signalling, recent structural findings that have altered our understanding of Mal signalling, and evidence that single nucleotide polymorphisms (SNPs) of Mal are responsible for variations in population level resistance and susceptibility to bacterial infection. © 2013 IUBMB Life, 65(9):777-786, 2013.
    International Union of Biochemistry and Molecular Biology Life 09/2013; 65(9):777-86. · 2.79 Impact Factor
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    ABSTRACT: An inducible program of inflammatory gene expression is central to antimicrobial defenses. Signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin modifying factors collaborate to control this response. Here, we identify a long noncoding RNA that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2 mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad acting regulatory component of the circuit that controls the inflammatory response.
    Science 08/2013; · 31.20 Impact Factor
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    ABSTRACT: In this study we describe a previously unreported function for NFκB2, an NFκB family transcription factor, in antiviral immunity. NFκB2 is induced in response to Poly(I:C), a mimic of viral dsRNA. Poly(I:C), acting via TLR3, induces p52-dependent transactivation of a reporter gene in a manner that requires the kinase activity of IKKε and the transactivating potential of RelA/p65. We identify a novel NFκB2 binding site in the promoter of the transcription factor Sp1 which is required for Sp1 gene transcription activated by Poly(I:C). We show that Sp1 is required for IL-15 induction by both Poly(I:C) and Respiratory Syncitial Virus, a response that also requires NFκB2 and IKKε. Our study identifies NFκB2 as a target for IKKε in anti-viral immunity and describes, for the first time, a role for NFκB2 in the regulation of gene expression in response to viral infection.
    Journal of Biological Chemistry 07/2013; · 4.65 Impact Factor
  • Anne F McGettrick, Luke A J O'Neill
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    ABSTRACT: The interplay between immunity, inflammation and metabolic changes is a growing field of research. Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are families of innate immune receptors and their role in our immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The pro-inflammatory cytokine IL-1β appears to play a central role in these disorders. There is also evidence for metabolites such as NAD+ (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates the transcription factor HIF1α) being signals which regulate innate immunity. In addition the over-production of metabolites extracellularly such as uric acid and cholesterol crystals act as signals sensed by NLRP3, leading to the production of IL-1β. These observations are casting new light on the role of metabolism during host defense and inflammation.
    Journal of Biological Chemistry 06/2013; · 4.65 Impact Factor
  • Caio T Fagundes, Luke A J O'Neill
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    ABSTRACT: A cyclic dinucleotide comprised of GMP and AMP was previously shown to be a key intermediate during activation of innate immune responses to cytosolic DNA. A report by Patel and Tuschl groups published in Cell reveals the structure of the enzyme involved in the synthesis of this second messenger and identifies this cyclic dinucleotide as a unique compound in metazoan cell signaling.
    Cell Research 06/2013; · 10.53 Impact Factor
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    ABSTRACT: Expression of the microRNA miR-223 is deregulated during influenza or hepatitis B infection and in Crohn's disease, type 2 diabetes, leukaemia and lymphoma. Although this may also be the result of the disease per se, increasing evidence suggests a role for miR-223 in limiting inflammation to prevent collateral damage during infection and in preventing oncogenic myeloid transformation. Validated targets for miR-223 that have effects on inflammation and infection include Granzyme B, IKKα, Roquin and STAT3. With regard to cancer, validated targets include C/EBPβ, E2F1, FOXO1 and NFI-A. The effect of miR-223 on these targets has been documented individually, however it is more likely that miR-223 affects multiple targets simultaneously for key processes where the microRNA is important. Such processes include haematopoietic cell differentiation, particularly towards the granulocyte lineage (where miR-223 is abundant) and as cells progress down the myeloid lineage (where miR-223 expression decreases). NF-κB and the NLRP3 inflammasome are important inflammatory mechanisms that are dampened by miR-223 in these cell types. The miRNA can also directly target viruses such as HIV, leading to synergistic effects during infection. Here we review the recent studies of miR-223 function to show how it modulates inflammation, infection and cancer development. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 06/2013; · 6.46 Impact Factor
  • Luke A J O'Neill, Douglas Golenbock, Andrew G Bowie
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    ABSTRACT: The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research.
    Nature Reviews Immunology 05/2013; · 32.25 Impact Factor
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    ABSTRACT: MyD88 adapter-like (Mal)-deficient mice displayed increased susceptibility to oral but not intraperitoneal infection with Salmonella Typhimurium. Bone marrow chimeras demonstrated that mice with Mal-deficient non-hematopoietic cells were more susceptible to infection, indicating a role for Mal in non-myeloid cells. We observed perturbed barrier function in Mal(-/-) mice, as indicated by reduced electrical resistance and increased mucosa blood permeability following infection. Altered expression of occludin, Zonula occludens-1, and claudin-3 in intestinal epithelia from Mal(-/-) mice suggest that Mal regulates tight junction formation, which may in part contribute to intestinal integrity. Mal interacted with several protein kinase C (PKC) isoforms in a Caco-2 model of intestinal epithelia and inhibition of Mal or PKC increased permeability and bacterial invasion via a paracellular route, while a pan-PKC inhibitor increased susceptibility to oral infection in mice. Mal signaling is therefore beneficial to the integrity of the intestinal barrier during infection.Mucosal Immunology advance online publication 24 April 2013. doi:10.1038/mi.2013.24.
    Mucosal Immunology 04/2013; · 7.54 Impact Factor
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    ABSTRACT: Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
    Nature 03/2013; · 38.60 Impact Factor
  • Luke A J O'Neill
    Science 02/2013; 339(6121):763-4. · 31.20 Impact Factor

Publication Stats

15k Citations
2,301.82 Total Impact Points

Institutions

  • 1995–2014
    • Trinity College Dublin
      • • Biochemistry
      • • School of Biochemistry and Immunology
      Dublin, Leinster, Ireland
    • Dublin City University
      • School of Biotechnology
      Dublin, Leinster, Ireland
  • 1994–2013
    • Trinity College
      • Biochemistry
      Hartford, Connecticut, United States
  • 2012
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • Coombe Women & Infants University Hospital
      Dublin, Leinster, Ireland
    • Radboud University Nijmegen
      • Department of General Internal Medicine
      Nijmegen, Provincie Gelderland, Netherlands
  • 2003–2012
    • University of Bath
      • Department of Pharmacy and Pharmacology
      Bath, ENG, United Kingdom
  • 2011
    • St. James's Hospital
      Dublin, Leinster, Ireland
    • University of Cambridge
      • Department of Biochemistry
      Cambridge, ENG, United Kingdom
  • 2005
    • University of Glasgow
      • Institute of Infection, Immunity and Inflammation
      Glasgow, SCT, United Kingdom